selectivity genotyping diagnostics

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expert. Huang was awarded the Nicholas Graduate Fellowship in Chemistry at Stanford. He is a member of the Biophysics Society and the American Chemical Society. He joined UCSD in 2002 and holds a patent. doi:10.1016/j.nano.2006.10.014

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Saturday, September 9th (10:50) Concurrent Symposium II: Genetic Nanomedicine

Modeling and control of gene delivery for gene therapy Zhang M, Life Science and Chemical Analysis Division, Agilent Technologies, Palo Alto, CA, USA Quantitative approach shows promising future for both fundamental nanomedicine research and advanced nanomedicine engineering. The first step for quantitative study of nanomedicine is modeling the physical, chemical, or biological processes involved at nanoscale. This presents a challenge in using proper mathematical techniques. A wrong mathematical model may not only create computational problems; but also lead to difficulties in controlling the system. The quantitative study of nanomedicine is a wide open subject. Less progress has been made due to lack of understanding on micro/nanoscale dynamics and the difficulties in integrating complex mathematical methods, system theory with biological principles. In this talk, we will first present fundamental mathematical elements and advanced system theory for modeling and control of micro/nanoscale biological and medical systems. In the second part, two examples are presented to illustrate the ideas. The first is on dynamics modeling of gene guns for gene therpy. A mathematical model is presented based on physical principles and micro/nano-scale dynamics of the gene delivery process. The second example is on modeling and control of electroporation-mediated gene delivery. Based on a presented mathematical model, advanced control strategy is proposed for effective gene delivery for gene therapy. Simulation results are presented for both examples to show the effectiveness of the approaches. The contributions of this research include systematic presentation of fundamental elements of mathematical system theory for micro/nanoscale dynamics modeling for gene delivery process, a practical dynamics model for gene delivery using gene guns, a computational efficient model and advanced control strategy for electroporation-mediated gene delivery. Mingjun Zhang received the D.Sc. degree from Washington University in St. Louis, and the Ph.D degree from Zhejiang University, P.R.China. He serves as an Associate Editor for the IEEE Transactions on Automation Science and Engineering, and was a lead guest editor for the journal’s Special Issue on Life Science Automation. He is currently working on the second Special Issue on Drug Delivery Automation. He is also a co-editor for the first book on Life Science Automation: Fundamentals and Applications, and the book of Systems Engineering Approach to Medical Automation. His research interests are mainly on quantitative approach to biosystems, including micro/nano-scale dynamics modeling and control for biological and medical systems, bioinstrumentation and life science automation. He was awarded the Early Career Award (industry) by the IEEE Robotics and Automation Society in 2003. doi:10.1016/j.nano.2006.10.015

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Saturday, September 9th (11:15) Concurrent Symposium II: Genetic Nanomedicine

Sequence-based pathogen diagnostics and surveillance Schnur J, Center for Bio/Molecular Science and Engineering, Naval Research Laboratory, Washington, DC The logarithmic accumulation of microbial genetic sequence information has invited its direct use in assays for both the detection and

detailed characterization of pathogens. Towards this, researchers at the Naval Research Laboratory have developed multi-pathogen identification systems using re-sequencing microarrays and computer algorithms for pathogen identification at strain level from partial sequence reads. In this presentation, Dr. Schnur will discuss: (1) methods for isolation and amplification of pathogen gene targets, (2) algorithms for identifying pathogens to a strain level using Basic Local Alignment Search Tool (BLAST)-based approaches, and (3) metropolitan medical surveillance applications. From Dr. Schnur’s early days at the NRL (Naval Research Laboratory) to the present, he has worked in a number of diverse areas to demonstrate the critically important ability to synergistically combine different areas of science to develop new ways of understanding the rules of nature and how to apply them to important problems. The success of the Center for Bio/Molecular science and Engineering (CBMSE) which he funded in 1984 has demonstrated the importance of bringing scientists together from different fields to combine their talents to create new science and technology, for example, by creating groups consisting of biologists, physicists, chemists, and engineers who have worked together. Dr Schnur’s personal research during this period has focused on bio/ molecular self assembly leading to the discovery, understanding, and applications of lipid derived sub micron hollow cylinders (called tubules). He is currently working on the modification and use of the photosynthetic reaction center found in plants to develop a system for highly efficient electron production from sunlight. In addition he is working in the area of bioinformatics and Resequencing based DNA probe arrays to develop broad spectrum, highly sensitive multiple pathogen arrays with the ability to sense and identify pathogens to strain level. doi:10.1016/j.nano.2006.10.016

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Saturday, September 9th (11:40) Concurrent Symposium II: Genetic Nanomedicine

Nanotech approaches to high sensitivity/selectivity genotyping diagnostics Heller MJ, Departments of Bioengineering/Electrical and Computer Engineering, University of California San Diego, 9500 Gilman Dr, San Diego, CA, USA A variety of microarray and other technologies have been developed for DNA genotyping research and diagnostics. For most of these genotyping (SNP’s STR’s, deletions, insertions) applications, some type of organic fluorophore is used to label the probes needed to detect and analyze the specific target DNA sequence within the sample. Nevertheless, after considerable time and development the detection of low copy number targets ( b 10,000) still remains problematic. Additionally, for many clinical genotyping diagnostic applications specificity and reliability can also be an issue. More recently, a variety of fluorescent nanoparticles called quantum dots have become available and are being used for biomolecule detection. Nevertheless, even with new nanoparticle labels which are intrinsically detectable at the single entity level, low copy number detection still remains elusive. We are now developing methods for creating luminescent, quantum dot and other fluorescent nanoparticle complexes that have the potential to overcome the specificity/sensitivity limitations seen in DNA genotyping applications. Michael J. Heller received his Ph.D. in Biochemistry from Colorado State University in 1973. He was an NIH Postdoctoral Fellow at Northwestern University from 1973 to 1976. Dr. Heller was supervisor of the DNA Technology Group at Amoco Corporation from 1976 to 1984, and then the Director of Molecular Biology at Molecular Biosystems, Inc., from 1984 to

Abstracts / Nanomedicine: Nanotechnology, Biology, and Medicine 2 (2006) 269–312 1987. He then went on to Integrated DNA Technologies, where he served as President and Chief Operating Officer from 1987 to 1989. He was the Chief Technical Officer at Nanogen, Inc., located in San Diego, California form 1993 to 2001. Dr. Heller is now a professor in the departments of Bioengineering and Electrical and Computer Engineering at the University California San Diego. He also serves as an exclusive consultant to Nanogen. Dr. Heller has extensive industrial experience in biotechnology; with particular expertise in the areas of DNA probe diagnostics, DNA synthesis, and fluorescent-based detection technologies. He has been the founder of several high technology companies. Nanogen Inc., the most recently formed is directed at the development of novel microelectronic DNA array technology. He has numerous patents and publications related to his work in biotechnology, DNA microarrays, medical diagnostics and nanotechnology. Dr. Heller has also served on several review panels for the National Nanotechnology Initiative. doi:10.1016/j.nano.2006.10.017

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Saturday, September 9th (10:00) Concurrent Symposium III: Drug Delivery Nanomedicine-1

New polymeric nanomedicines for targeted and controlled drug delivery Hanes J, Biomedical Engineering and Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Institute for NanoBioTechnology at Johns Hopkins, Johns Hopkins University, Baltimore, MD, USA Targeted drug delivery can significantly improve drug effectiveness at lower doses while reducing side effects by concentrating medicine at selected sites in the body. However, drug and gene delivery to target tissues is currently limited by a lack of suitable polymeric materials and inefficient nanoparticle transport within complex extra- and intracellular biological environments. This talk will focus on our development of a new family of polymers, the poly(ether-anhydrides), designed to be selectively adhesive to desired cell types, and non-adhesive to obstacles in the body that might prevent their targeted delivery, such as proteins in blood and mucus layers. The unique properties of the polymer allow for highly targeted deposition of nanoparticles in the body, either within the lungs via inhaled aerosols, or within a specific tissue following injection into the blood. Nanoparticles made with this new polymer: (i) show up to 10-fold selective adhesion to targeted versus non-targeted tissues in vivo, and (ii) are capable of surprisingly fast transport in highly viscoelastic mucus layers that typically serve to trap and efficiently remove particles, a trait that allows the drug carrying nanoparticles to avoid rapid clearance in the lungs. Poly(etheranhydride) nanoparticles are also capable of efficient uptake by targeted cells and motor protein mediated active transport to the cell nucleus (target site for several drug and gene therapies). Perinuclear delivery by poly(etheranhydride) nanoparticles is shown to make doxorubicin, a common chemotherapeutic agent, more effective at lower doses. Justin Hanes is Associate Professor of Chemical and Biomolecular Engineering, Biomedical Engineering, and Oncology at Johns Hopkins, where he is also a member of the executive committee and Director of Nanotherapeutics at the Institute for NanoBioTechnology. Recently, there were at least ten products in clinical or preclinical trials based on Justin’s and his colleagues’ inventions, for which he owns 15 patents. Justin has been named among the bWorld’s Top 100 Young Innovators,Q by the MIT Technology Review and will be one of two invited speakers on the topic of bNanomedicineQ at the National Academies of Science 2006 meeting this October. doi:10.1016/j.nano.2006.10.018

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Saturday, September 9th (10:25) Concurrent Symposium III: Drug Delivery Nanomedicine-1

Nanoparticle delivery into biological tissues by ultrasonic microbubble destruction Price R, Chappell J, Song J, Klibanov A, University of Virginia, Richmond, VA, USA The delivery of circulating drug and gene bearing nanoparticles (NPs) to tissue with minimal side-effects represents a considerable challenge. We have shown that contrast agent microbubbles (MBs), which are typically used for image enhancement in diagnostic ultrasound (US), can be used to selectively permeabilize capillaries and permit the transport of intravascular NPs to ultrasound targeted tissues. To develop an US-MB based delivery method for therapeutic angiogenesis, we applied US to arterially occluded mouse hindlimb following MB and fluorescent 100 nm polystyrene and poly(lactide-co-glycolide) NP injection. NP deposition in muscle tissue was confirmed by confocal imaging of whole-mounted and cross-sectioned muscles. US-MB interactions delivered NPs into the microvessel wall as well as into the interstitium. Applying US alone appears to transfer NPs only into the walls of vessels and not into the interstitium, and administering MBs without US causes minimal to no NP deposition. Specifically, US with MBs leads to 4.5 times the NP deposition when compared to US alone, and 152 times more than using MBs alone. In future studies, we will investigate if nanoparticles are internalized by vascular and muscle cells and if controlled release NPs bearing therapeutic agents might be delivered to unhealthy tissues for prolonged treatment. These investigations demonstrate the potential for developing therapies in which biodegradable NPs carrying therapeutic drugs or genes could be delivered noninvasively to a targeted tissue for the controlled release of their contents. Dr. Richard J. Price is an Associate Professor of Biomedical Engineering at the University of Virginia. His applied research focus is on the development of minimally invasive ultrasound-based methods for stimulating blood vessel growth, with the goal of restoring blood flow to tissues and organs affected arterial occlusion and atherosclerosis. His work has been published in high impact journals such as Circulation, Circulation Research, and the Journal of the American College of Cardiology. He is an elected member of the Executive Council of the Microcirculatory Society and is an Associate Editor for Microcirculation. He served as a grant reviewer for the National Institutes of Health, the German-Israeli Foundation for Scientific Research and Development, and the Austrian Science Foundation. Dr. Price has secured $4.9 M in total grant funding from the National Institutes of Health, the Whitaker Foundation, and the American Heart Association. doi:10.1016/j.nano.2006.10.019

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Saturday, September 9th (10:50) Concurrent Symposium III: Drug Delivery Nanomedicine-1

CYT-6091 (Aurimune): a colloidal gold-based tumor-targeted nanomedicine Tamarkin L, Myer L, Haynes R, Paciotti G, CytImmune Sciences, Inc, Rockville, MD, USA Targeting potent anti-cancer therapeutics to solid tumors is best accomplished by first avoiding recognition and uptake by the immune system and second by limiting the biodistribution of the drug to the tumor. We have achieved these objectives by binding tumor necrosis factor alpha (TNF) to the surface of 30 nm pegylated colloidal gold particles. Pegylation of the gold nanoparticles is accomplished by binding thiolated polyethylene glycol in between the TNF molecules on the surface of the gold nanoparticles. This formulation is termed CYT-6091 (Aurimune). The liver